We propose to upgrade the siRNA Screening System at the High-Throughput Bioscience Center (HTBC), a core facility that supports high-throughput (HT) research at Stanford University. Genomic-scale siRNA (small interfering RNA) screening with HT imaging has emerged as a particularly promising tool for functional genomic research. The proposed upgrades would significantly enhance the HTBC's capabilities by permitting automated cellular imaging in conjunction with efficient and reliable siRNA transfections. Currently, researchers at the HTBC can perform fully automated HT spectrophotometric small molecule screens, but cannot efficiently run HT siRNA and high-content image-based screens. The proposed instrumentation enhancements will allow for efficient siRNA screening by integrating and upgrading the siRNA liquid handling and detection capabilities. These upgrades will enable near-seamless execution of imaged-based siRNA screens, from the initial siRNA transfections to the final plate imaging. To make siRNA transfections more reliable and efficient we propose to upgrade the Velocity11 liquid handling system to a full time 384-well plate format with improved plate handling, tracking, and reagent dispensing. This system can then be integrated to our existing ImageXpress Micro (Molecular Devices) epifluorescence microscope workstation via a robotic arm. Additional upgrades to this microplate imaging platform include adding transmitted light capabilities, integration to an automated incubator, and updating/replacing the image database servers. In sum this upgraded siRNA Screening System will further expedite high-content, genome-wide siRNA screens at Stanford University and its neighboring institutions. These improvements will impact other HT screening activities at the HTBC as well, including chemical and cDNA library screens for the identification of small molecule and genetic modulators of specific biological processes.